Aminoacyllabdanes, pharmacuetical compositions and use

ABSTRACT

Novel aminoacyllabdanes, intermediates and processes for the preparation thereof, and methods for reducing intraocular pressure utilizing compounds or compositions thereof are disclosed.

This is a division of application Ser. No. 804,405 filed Dec. 4, 1985now U.S. Pat. No. 4,639,446 which is a continuation-in-part ofapplication Ser. No. 681,779, filed Dec. 14, 1984, now abandoned.

The present invention relates to aminoacyllabdanes. More particularly,the present invention relates to aminoacyllabdanes of Formula 1 ##STR1##wherein R₁ is R₂ R₃ NCHR₄ CO wherein R₂ is hydrogen, loweralkyl orbenzyl, R₃ is hydrogen or loweralkyl and R₄ is hydrogen, loweralkyl orbenzyl; R₂ and R₃ taken together with the nigrogen atom to which theyare attached form a group of the formula ##STR2## wherein X is CO, O, S,SO, SO₂ ; a group of the formula CHR₉ wherein R₉ is hydrogen, loweralkylor a group of the formula OR₁₀ wherein R₁₀ is hydrogen or COR₁₁ whereinR₁₁ is loweralkyl; or a group of the formula NR₁₂ wherein the R₁₂ isloweralkyl; n is 0 or 1; R₆ is hydrogen or a group of the formula R₅ COwherein R₅ is hydrogen or loweralkyl; R₇ is hydrogen or a group of theformula R₈ CO wherein R₈ is hydrogen or loweralkyl; and R₆ and R₇ takentogether form a group of the formula CO or SO; the optical and geometricisomers thereof, or a pharmaceutically acceptable acid addition saltthereof, which are useful for reducing intraocular pressure, alone or incombination with inert adjuvants.

Subgeneric to the aminoacyllabdanes of the present invention arecompounds of formula 1 wherein:

(a) R₂ and R₃ are hydrogen or loweralkyl;

(b) R₂ is hydrogen and R₃ is loweralkyl;

(c) R₂ and R₃ taken together with the nitrogen atom to which they areattached form a group of the formula ##STR3## wherein X is CO, O, S, SO,SO₂ ; a group of the formula CHR₉ wherein R₉ is hydrogen, loweralkyl ora group of the formula OR₁₀ wherein R₁₀ is hydrogen or COR₁₁ wherein R₁₁is loweralkyl; or a group of the formula NR₁₂ wherein R₁₂ is loweralkyl;and n is 0 or 1;

(d) R₄ is hydrogen or loweralkyl;

(e) R₄ is benzyl;

(f) R₆ and R₇ taken together form a group of the formula CO or SO;

(g) R₆ is hydrogen or a group of the formula R₅ CO wherein R₅ ishydrogen or loweralkyl; and

(h) R₇ is hydrogen or a group of the formula R₈ CO wherein R₈ ishydrogen or loweralkyl.

The present invention also relates to compounds of formula 2 ##STR4##wherein R₄ is hydrogen, loweralkyl or benzyl; R₆ is hydrogen or a groupof the formula R₅ CO wherein R₅ is hydrogen or loweralkyl; R₇ ishydrogen or a group of the formula R₈ CO wherein R₈ is hydrogen orloweralkyl; Hal is chloro or bromo; or the optical and geometric isomersthereof, which are useful as intermediates for the preparation of theaminoacyllabdanes of the present invention.

A compound of formula 2 wherein Hal is bromo is preferred.

As used through the specification and appended claims, the term "aklyl"refers to a straight or branched chain hydrocarbon radical containing nounsaturation and having 1 to 8 carbon atoms such as methyl, ethyl,1-propyl, 2-propyl, 2-methylpropyl, 1-pentyl, 2-pentyl, 3-hexyl,4-heptyl, 2-octyl, and the like; the term "alkanol" refers to a compoundformed by a combination of an alkyl group and a hydroxy radical.Examples of alkanols are methanol, ethanol, 1- and 2-propanol,1,2-dimethylethanol, hexanol, octanol and the like. The term "alkanoicacid" refers to a compound formed by combination of a carboxyl groupwith a hydrogen atom or alkyl group. Examples of alkanoic acids areformic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid,hexanoic acid, octanoic acid and the like; the term "halogen" refers toa member of the family consisting of fluorine, chlorine, bromine oriodine. The term "alkanoyl" refers to the radical formed by removal ofthe hydroxyl function from an alkanoic acid. Examples of alkanoyl groupsare formyl, acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyland the like. The term "lower" as applied to any of the aforementionedgroups refers to a group having a carbon skeleton containing up to andincluding 6 carbon atoms.

In the formulas presented herein the various substitutents areillustrated as joined to the labdane nucleus by one of two notations: asolid line (--) indicating a substituent which is in the β-orientation(i.e., above the plane of the molecule) and a broken line ( ) indicatinga substituent which is in the α-orientation (i.e., below the plane ofthe molecule). The formulas have all been drawn to show the compounds intheir absolute stereochemical configuration. Inasmuch as the startingmaterials having a labdane nucleus are naturally occurring or arederived from naturally occurring materials, they, as well as the finalproducts, have a labdane nucleus existing in the single absoluteconfiguration depicted herein. The processes of the present invention,however, are intended to apply as well to the synthesis of labdanes ofthe racemic series.

In addition to the optical centers of the labdane nucleus, thesubstituents thereon may also contain chiral centers contributing to theoptical properties of the compounds of the present invention andproviding a means for the resolution thereof by conventional methods,for example, by the use of optically active acids. The present inventioncomprehends all optical isomers and racemic forms of the compounds ofthe present invention, where such compounds have chiral centers inaddition to those of the labdane nucleus.

The novel aminoacyllabdanes of the present invention are synthesized bythe processes illustrated in the Reaction Scheme.

To prepare an aminoacyllabdane 4 wherein R₇ is alkanoyl, a1-hydroxylabdane 3 wherein R₇ is alkanoyl is acylated with ahaloalkylcarbonyl halide of formula 8

    HalCHR.sub.4 COHal                                         8

wherein R₄ and Hal are as hereinbeforedescribed to provide a1-haloalkanoyloxyladane 2 which is condensed with an amine of formula 9

    R.sub.2 R.sub.3 NH                                         9

to afford 4.

The acylation of hydroxylabdane 3 is readily accomplished by treating ahydroxylabdane 3 with a haloalkylcarbonyl halide 8 such as abromoalkylcarbonyl bromide or a chloroalkylcarbonyl chloride, abromoalkylcarbonyl bromide being preferred, in a halocarbon in thepresence of a tertiary amine. Among halocarbons, there may be mentioneddichloromethane, trichloromethane, 1,1- and 1,2-dichloromethane and 1,1-and 1,2-dichloroethene. Dichloromethane is the preferred halocarbon.Among tertiary amines, there may be mentioned, for example,4-dimethylaminopyridine and N,N-dimethylaniline. N,N-Dimethylaniline isthe preferred amine. While the temperature at which the acylation isperformed is not narrowly critical, it is preferred to conduct thereaction at a temperature within the range of about -0° to about 50° C.It is most preferred to perform the acylation at a temperature withinthe range of about 0° to about 25° C.

The condensation is effected by treating a haloalkanoyloxylabdane 2 witha primary or secondary amine 9 in and alkyl alkanoate or halocarbon, ora mixture thereof. Included among alkyl alkanoates are methyl acetate,ethyl acetate and ethyl propanoate. Included among halocarbons aredichloromethane, trichloromethane, 1,1- and 1,2-dichloromethane. Ethylacetate and dichloromethane are the preferred solvents. The condensationis preferably performed in the absence of added base. An alkali metalbicarbonate such as lithium, sodium or potassium bicarbonate may,however, be utilized. The condensation temperature is not critical. Theconversion proceeds readily at a temperature within the range of about0° to about 50° C. A reaction temperature of about 25° C. is preferred.

To provide an aminoacyllabdane 5 wherein R₆ is alkanoyl, aminoacylabdane4 may be rearranged, for example, by treating 4 with lithium,1,1,1,3,3,3-hexamethyldisilazide in an ethereal solvent such astetrahydrofuran at a temperature of about 0° C.

To provide an aminoacyllabdane 6 having free 6β,β-hydroxy groups, onemay treat 1α, 6β,7β,9α-tetrahydroxylabdane 3 wherein R₇ is hydrogen witha haloalkylcarbonyl halide 8 under reaction conditions substantiallysimilar to those employed for the conversion of trihydroxylabdane 3wherein R₇ is alkanoyl to aminoacylabdane 4 wherein R₇ is alkanoyl.

To synthesize an aminoacyllabdane 8 wherein R₆ and R₇ are alkanoyl, onemay acylate an aminoacyllabdane 5 with an alkanoic acid of formula 10

    R.sub.5 (R.sub.8)CO.sub.2 H                                10

wherein R₅ and R₈ are as hereinbeforedescribed, an anhydride thereof offormula 11 ##STR5## wherein R₅ and R₈ are as hereinbeforedescribed, ormixtures thereof, or the halide thereof of formula 12

    R.sub.5 (R.sub.8) COHal                                    12

wherein R₅, R₈ and Hal are as hereinbeforedescribed. The acylation maybe performed in the presence of a basic catalyst such as, for example,pyridine, lutidine or collidine at a reduced temperature within therange of about 0° to 25° C.

In the event a carboxylic acid of formula 10 is employed in theacylation step, a carbodiimide such as, for example,dicyclohexylcarbodiimide, may be utilized.

Aminoacyllabdanes of formula 7 wherein Y is CO or SO may be prepared bytreating a dihydroxylabdane 6 with a compound of formula 13

    Hal-Y-Hal                                                  13

wherein Y is CO or SO and Hal is as hereinbeforedescribed in thepresence of an aromatic amine such as pyridine, lutidine or s-collidineat a reduced temperature of about -10° to about 10° C.

The labdane starting materials for the processes of the presentinvention, i.e., labdanes of formula 3 wherein R₇ is hydrogen or a groupof the formula R₈ CO wherein R₈ is hydrogen or alkyl, are described inU.S. Pat. No. 4,134,986, issued Jan. 16, 1979 to B. S. Bajwa, et al.

The aminoacyllabdanes of the present invention are useful in thetreatment of elevated intraocular pressure by virtue of their ability toreduce intraocular pressure as determined by the method described by J.Caprioli, et al., Invest. Ophthalmol. Vis. Sci., 25, 268 (1984). Theresults of the determination expressed as percent decrease of outflowpressure is presented in the Table.

                  TABLE                                                           ______________________________________                                                                    DECREASE IN                                                       CONCEN-     OUT-FLOW                                          COMPOUND        TRATION (%) PRESSURE (%)                                      ______________________________________                                        7β-acetoxy-8,13-epoxy-                                                                   1.0         66                                                1α-diethylaminoacetoxy-                                                                 0.1         30                                                6β,9α-dihydroxylabd-14-en-                                         11-one                                                                        7β-acetoxy-8,13-epoxy-                                                                   1.0         63                                                1α-[(morpholin-4-yl)acetoxy-                                            6β,9α-dihydroxylabd-14-en-                                         11-one                                                                        7β-acetoxy-8,13-epoxy-                                                                   1.0         51                                                1α,6β,9α-trihydroxylabd-                                                     0.1         23                                                14-en-11-one                                                                  ______________________________________                                    

Intraocular pressure reduction is achieved when the presentaminoacyllabdanes are administered to a subject requiring such treatmentas an effective topical dose of a 0.01 to 3.0% solution or suspension. Aparticularly effective amount is about 3 drops of a 1% preparation perday. It is to be understood, however, that for any particular subject,specific dosage regimens should be adjusted according to the individualneed and the professional judgement of the person administering orsupervising the administration of the aforesaid compound. It is to befurther understood that the dosages set forth herein are exemplary onlyand that they do not, to any extent, limit the scope or practice of theinvention.

Compounds of the present invention include:

(a)7β-Acetoxy-1α-(2-aminopropionyloxy)-8,13-epoxy-6β,9α-dihydroxylabd-14-en-11-one;

(b)7β-Acetoxy-1α-[2-(N-benzylamino)propionyloxy]-8,13-epoxy-6.beta.,9α-dihydroxylabd-14-en-11-one;

(c)7β-Acetoxy-8,13-epoxy-1α-[2-(N-ethylamino)propionyloxy]-6β,9α-dihydroxylabd-14-en-11-one;

(d)7β-Acetoxy-8,13-epoxy-1α-[2-(N-ethylamino)-3-phenylpropionyloxy]-6β,9α-dihydroxylabd-14-en-11-one;

(e)6β-Acetoxy-8,13-epoxy-7β,9α-dihydroxy-1α-(dimethylaminoacetoxy)labd-14-en-11-one;

(f)7β-Acetoxy-8,13-epoxy-6β-formyloxy-9α-hydroxy-1α-(dimethylaminoacetoxy)labd-14-en-11-one;

(g)8,13-Epoxy-7β-formyloxy-6β,9α-dihydroxy-1α-(dimethylaminoacetoxy)labd-14-en-11-one;

(h)8,13-Epoxy-6β,7β,9-trihydroxy-1α-(dimethylaminoacetoxy)labd-14-en-11-onecarbonate;

(i) 8,13-Epoxy-6β,7β,9α-trihydroxy-1α-(dimethylaminoacetoxy)labd-14-en-11-one sulfite.

The aminoacyllabdanes of the present invention are also useful in thetreatment of hypertension, congestive heart failure, bronchial asthmaand psoriasis.

Effective amounts of the compounds of the present invention may beadministered to a subject by any one of various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, in some cases intravenously in the form ofsterile solutions, or suspensions, and topically in the form ofsolutions, suspensions or ointments, and by aersol spray. Theaminoacyllabdanes of the present invention, while effective themselves,may be formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of increased solubility and thelike.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid and thelike, and salts of tribasic carboxylic acids such as, for example,citric acid and the like.

Effective quantities of the compounds of the invention may beadministered orally, for example, with an inert diluent or with anedible carrier. They may be enclosed in gelatin capsules or compressedinto tablets. For the purpose of oral therapeutic administration, theaforesaid compounds may be incorporated with excipients and used in theform of tablets, troches, capsules, elixirs, suspensions, syrups,wafers, chewing gums and the like. These preparations should contain atleast 0.5% of active compounds, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of active compound in such composition issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that anoral dosage unit form contains between 0.1-30 milligrams of the activecompound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragancanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, corn starch and the like; alubricant such as magnesium stearate; a glidant such as colloidalsilicon dioxide; and a sweetening agent such as sucrose or saccharin ora flavoring agent such as peppermint, methyl salicylate, or orangeflavoring may be added. When the dosage unit form is a capsule, it maycontain, in addition to materials of the above type, a liquid carriersuch as a fatty oil. Other dosage unit forms may contain other variousmaterials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral or topical therapeutic administration,the active compounds of the invention may be incorporated into asolution, suspension, ointment or cream. These preparations shouldcontain at least 0.01% of active compound, but may be varied between 0.5and about 5% of the weight thereof. The amount of active compounds insuch compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations according to the presentinvention are prepared so that a parenteral or topical dosage unitcontains between 0.01 to 10 milligrams of active compound.

The solutions or suspensions for topical or parenteral administrationmay also include the following components: a sterile diluent such aswater for injection, saline solution, fixed oils, polyethylene glycols,glycerine, propylene glycol or other synthetic solvents; antibacterialagents such as benzyl alcohol or methyl parabens; antioxidants such asascorbic acid or sodium bisulfite; chelating agents such asethylenediaminetetraacetic acid; buffers such as acetates, citrates orphosphates and agents for the adjustment of tonicity such as sodiumchloride or dextrose. The parenteral preparation can be enclosed inampules or disposable syringes; the topical preparation may be enclosedin multiple dose vials or dropping bottles, made of glass or plastic.

All temperatures are given in degrees Centigrade.

EXAMPLE 17β-Acetoxy-8,13-epoxy-1α-(diethylaminoacetoxy)-6β-9α-dihydroxylabd-14-en-11-onehydrochloride

To 200 mg of 7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-onewas added a solution of 0.70 ml of N,N-dimethylaniline in 1 ml of dry(3A molecule sieves) dichloromethane. The solution, under nitrogen, wascooled in an ice bath. To the solution was added slowly, dropwise, asolution of 0.050 ml of bromoacetyl bromide. The mixture was stirred 2hrs at ice bath temperature and 1 hr at room temperature. The mixturewas diluted with ethyl acetate, washed with sodium bicarbonate solutionand water, and dried over anhydrous sodium sulfate. Filtration followedby evaporation of the solvent provided an oil. The oil was dissolved in3 ml of ethyl acetate. To the solution was added 0.068 mg of sodiumbicarbonate and a solution of 0.050 ml of diethylamine in 1 ml of ethylacetate. The mixture was stirred 0.5 hr at 80°, allowed to cool to roomtemperature and filtered. The filtrate was diluted with ethyl acetate,washed with water, saturated sodium chloride solution and dried overanhydrous sodium sulfate. Filtration followed by evaporation of solventprovided an oil. The oil was dissolved in a minimum volume of 70/30hexane/ethyl acetate and chromatographed on 50 g of silica gel (230-400mesh, nitrogen pressure, eluent: 30×15 ml of 70/30 hexane/ethylacetate). The appropriate fractions were concentrated and the solventevaporated to provide 129 mg (50.5%) of product as an oil. Thehydrochloride was precipitated/crystallized from ether to provideproduct as the hydrochloride, mp 160°-165°.

Analysis: Calculated for C₂₈ H₄₅ NO₈ HCl: 60.04%C, 8.28%H, 2.50%N,Found: 59.79%C, 7.93%H, 2.44%N.

EXAMPLE 27β-Acetoxy-8,13-epoxy-1α-(dimethylaminoacetoxy)-6β,9α-dihydroxylabd-14-en-11-onehydrochloride

To 100 mg of 7β-acetoxy-8,13-epoxy-1α, 6β,9α-trihydroxylabd-14-en-11-onewas added a solution of 0.035 ml of N,N-dimethylaniline in 1 ml of drydichloromethane. The solution was cooled in an ice bath. To the solutionwas added slowly, dropwise, a solution of 0.025 ml of bromoacetylbromide in 1 ml of dry dichloromethane. The mixture was stirred 1 hr atice bath temperature and allowed to warm to room temperature. Themixture was diluted with ethyl acetate, washed with sodium bicarbonatesolution, water and dried over anhydrous sodium sulfate. Filtrationfollowed by evaporation of the solvent provided an oil. The oil wasdissolved in 2 ml of ethyl acetate. To the solution was added 1 ml ofethyl acetate which had been saturated with dimethylamine (gas). Thesolution was stirred at room temperature for 15 min, diluted with ethylacetate, washed with sodium bicarbonate solution, saturated sodiumchloride solution and dried over anhydrous sodium sulfate. Filtrationfollowed by evaporation of solvent provided an oil. The oil waschromatographed on silica gel (20 g, 230-400 mesh; eluent: 50×15 ml of70/30 hexane/ethyl acetate). Evaporation of the appropriate fractionsprovided 93 mg (76.6%) of product as an oil, which upon addition ofethereal hydrogen chloride, precipitated the hydrochloride, mp156°-182°.

Analysis: Calculated for C₂₆ H₄₁ NO₈ HCl: 58.69%C, 7.69%H, 2.63%N,Found: 58.55%, 8.06%H, 2.56%N.

EXAMPLE 37β-Acetoxy-8,13-epoxy-1α-[(pyrrolidin-1-yl)]acetoxy]-6β,9.alpha.-dihydroxylabd-14-en-11-onehydrochloride

To a stirred solution of 100 mg of7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in 1 ml ofdry dichloromethane and 0.035 ml of N,N-dimethylaniline at 0°, undernitrogen, was added dropwise a solution of 0.025 ml of bromoacetylbromide in 1 ml of dry dichloromethane. The mixture was allowed to warmto room temperature, diluted with ethyl acetate, washed with sodiumbicarbonate solution, water and dried over anhydrous sodium sulfate. Thesolution was filtered and concentrated to an oil. The oil was dissolvedin 3 ml of ethyl acetate and added to a stirred solution of 0.1 g ofpyrrolidine in 1 ml of ethyl acetate. The mixture was stirred 0.5 hr atroom temperature, diluted with ethyl acetate, extracted twice with ethylacetate, washed three times with water, once with saturated sodiumchloride solution, dried over sodium sulfate, filtered and the solventevaporated to provide an oil. The oil was dissolved in a minimum volumeof 70% ethyl acetate/hexane, and flashed chromatographed on 50 g ofsilica gel (230-400 mesh; 75×15 ml). Concentration of the appropriationfractions provided an oil. The oil was dissolved in anhydrous ether andthe hydrochloride precipitated to provide 50.5 mg (37.1%) of product, mp148-158.

Analysis: Calculated for C₂₈ H₄₃ NO₈ HCl: 60.25%C, 7.95%H, 2.51%N,Found: 60.64%C, 8.29%H, 2.50%N.

EXAMPLE 47β-Acetoxy-8,13-epoxy-1α-[(morpholin-4-yl)acetoxy]-6β,9.alpha.-dihydroxylabd-14-en-11-onehydrochloride

To a stirred solution of 109 mg of 7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in 1 ml of dry dichloromethanecontaining 0.038 ml of dimethylamiline in an ice bath was added dropwisea solution of 0.029 ml of bromoacetyl bromide in one ml of drydichloromethane. The mixture was stirred at ice bath temperature for onehr, diluted with ethyl acetate, washed with water, saturated sodiumbicarbonate solution, water and dried over anhydrous sodium sulfate.Filtration followed by evaporation of solvent provided an oil which wasdissolved in 2 ml of dry dichloromethane and added to a solution of 0.1g of morpholine in 2 ml of ethyl acetate. The mixture was stirred 1 hrat room temperature, diluted with ethyl acetate, washed with water,saturated sodium bicarbonate solution, water and dried over anhydroussodium sulfate. The solution was filtered and concentrated to an oil.The oil was dissolved in a minimum volume of 1/1 ethyl acetate/hexaneand flash chromatographed on silica gel (230-400 mesh) (eluent: 20×15 mlof 1/1 ethyl acetate/hexane). The appropriate fractions were combinedand concentrated to an oil. The oil was dissolved in ether andprecipitated with ethereal hydrogen chloride to provide 67.3 mg (61.7%)of product as the hydrochloride, mp 153°-163°.

Analysis: Calculated for C₂₅ H₄₃ NO₉ HCl: 58.57%C, 7.73%H, 2.44%N,Found: 58.99%C, 7.69%H, 2.14%N.

EXAMPLE 57β-Acetoxy-8,13-epoxy-1α-[(di-n-propylamino)acetoxy]-6β,9.alpha.-dihydroxylabd-14-en-11-onehydrochloride

To a stirred solution of 108 mg of7β-acetoxy-8,13-epoxy-1α,9β,9α-trihydroxylabd-14-en-11-one in a solutionof 1 ml of dry dichloromethane containing 0.038 ml of dimethylaniline,in an ice bath, under nitrogen, was added slowly dropwise a solution of0.027 ml of bromoacetyl bromide in 1 ml of dry dichloromethane. Themixture was stirred at 0° for 1 hr, allowed to warm to room temperature,diluted with ethyl acetate, washed with cold water, saturated sodiumbicarbonate solution and dried over anhydrous sodium sulfate. Filtrationfollowed by evaporation of solvent provided an oil. The oil wasdissolved in 1 ml of dichloromethane and added to a stirred solution of0.1 g of di-n-propylamine in 1 ml of ethyl acetate. The solution wasstirred 1 hr at room temperature and extracted with ether. The extractswere washed twice with water, once with saturated sodium chloridesolution and dried over anhydrous sodium sulfate. Filtration followed byevaporation of solvent provided an oil. The oil was dissolved in aminimum volume of 20% ethyl acetate/hexane and flash chromatographed on25 g of silica gel (230-400 mesh) (eluent: 25×10 ml of 20% ethylacetate/hexane). Concentration of the appropriate fractions provided anoil. Addition of ethereal hydrogen chloride to an ethereal solution ofthe oil provided 59.9 mg (38.8%) of product as the hydrochloride, mp199°-202°.

Analysis: Calculated for C₃₀ H₄₉ NO₈ HCl: 61.26%C, 8.57%H, 2.38%N,Found: 61.08%C, 8.46%H, 2.26%N.

EXAMPLE 68,13-Epoxy-1-(diethylaminoacetoxy)-6β,7β,9α-trihydroxylabd-14-en-11-onehydrochloride

A solution of 200 mg of7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in 10 ml of asat potassium carbonate solution in 20% aqueous methanol was stirred 2hr at 25°-28°. The mixture was diluted with ethyl acetate, washed twicewith water, once with saturated sodium chloride solution, dried overanhydrous sodium sulfate, filtered and concentrated to provide 157 ml of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one as an oil.

To a stirred solution of 157 mg of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one, 0.0593 ml ofN,N-dimethylaniline and 1 ml of dry dichloromethane in an ice bath,under nitrogen, was added dropwise a solution of 0.0421 ml ofbromoacetyl bromide in 1 ml of dry dichloromethane. The mixture wasstirred 1 hr at 0°, poured into ice water/ethyl acetate, washed withcold sat sodium bicarbonate solution, water and dried over anhydroussodium sulfate. Filtration followed by evaporation of solvent providedan oil. The oil was dissolved in 1 ml of dry dichloromethane and addedto a stirred solution of 0.1 g of diethylamine in 1 ml of ethyl acetate.The solution was stirred for 1 hr at ambient temperature and extractedwith ethyl acetate. The extract was washed with water, saturated sodiumchloride solution and dried over anhydrous sodium sulfate. Filtrationfollowed by evaporation provided an oil. The oil was dissolved in aminimum volume of 1/1 ethyl acetate/hexane and flash chromatographed on20 g of silica gel (230-400 mesh) (eluent: 25×10 ml of 1/1 ethylacetate/hexane). Concentration of the appropriate fractions provided anoil, the hydrochloride of which was precipitated from ether to yield90.2 mg (42.4%) of product, mp 127°-157°.

Analysis: Calculated for C₂₆ H₄₃ NO₇ HCl: 60.27%C, 8.56%H, 2.70%N,Found: 59.99%C, 8.74%H, 2.58%N.

EXAMPLE 77β-Acetoxy-8,13-epoxy-1α-[(4-hydroxypiperidin-1-yl)acetoxy]-6.beta.,9α-dihydroxylabd-14-en-11-onehydrochloride

To a stirred solution of 106 mg of7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in 1 ml ofdry dichloromethane containing 0.038 ml of dimethylaniline, in an icebath, was added dropwise a solution of 0.027 ml of bromoacetyl bromidein 1 ml of dry dichloromethane. The mixture was stirred at 0° for 1 hr,allowed to warm to room temperature, poured onto ice sodium bicarbonateethyl acetate, extracted with ethyl acetate, washed with water and driedover anhydrous sodium sulfate. Filtration followed by evaporation ofsolvent provided an oil which was dissolved in 1 ml of dichloromethaneand added to a stirred solution of 0.10 g of 4-hydroxypiperidine in 1 mlof ethyl acetate. The mixture was stirred 1 hr at room temperature,poured onto ice/water ethyl acetate, extracted with ethyl acetate,washed with water, saturated sodium chloride solution and dried overanhydrous sodium sulfate. Filtration followed by evaporation of thesolvent provided an oil. The oil was dissolved in a minimum volume of30% ethyl acetate/hexane and flash chromatographed on 25 g of silica gel(230-400 mesh). Concentration of the appropriate fractions gave an oil.Treatment of the oil with ethereal hydrogen chloride gave 0.109 g(76.4%) of product as the hydrochloride, mp 166°-189°.

EXAMPLE 87β-Acetoxy-8,13-epoxy-1α-[(thiomorpholin-4-yl)acetoxy]-6β,9α-dihydroxylabd-14-en-11-one

To a stirred solution of 104 mg of7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one containing0.037 ml of N,N-dimethylaniline in 1 ml of dry dichloromethane at 0°under nitrogen was added dropwise a solution of 0.026 ml of bromoacetylbromide. The mixture was stirred 1 hr at 0°, allowed to warm to roomtemperature, poured onto ice, extracted with ethyl acetate, washed withanhydrous sodium sulfate, filtered, and the filtrate concentrated to anoil. The oil was dissolved in 1 ml of dry dichloromethane and thesolution was added dropwise to a solution of 0.1 g of thiomorpholine in1 ml of ethyl acetate. The mixture was stirred 1.5 hr, poured onto ice,diluted with ethyl acetate, washed with water, saturated sodium chlorideand dried over anhydrous sodium sulfate. Filtration followed byevaporation of solvent and purification by flash chromatography to yieldan oil. The oil was dissolved in ether and ethereal hydrogen chloridewas added to provide 69.1 mg (47.8%) of product, as the hydrochloride,mp 161°-171°.

EXAMPLE 97β-Acetoxy-8,13-epoxy-1α-[(piperidin-1-yl)acetoxy]-6β,9.alpha.-dihydroxylabd-en-11-onehydrochloride

To a stirred solution of 104 mg of7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in 1 ml ofdry dichloromethane containing 0.037 ml of dimethylaniline in an icebath, was added slowly, dropwise, a solution of 0.026 ml of bromoacetylbromide in 1 ml of dry dichloromethane. The mixture was stirred for 1 hrat ice bath temperature, allowed to warm to room temperature, dilutedwith ethyl acetate, poured into ice/water, extracted with ethyl acetate,washed with cold, saturated sodium bicarbonate solution, water, anddried over anhydrous sodium sulfate. Filtration followed by evaporationof the solvent provided an oil which was dissolved in 1.5 ml ofdichloromethane and added dropwise to a stirred solution of 0.1 g ofpiperidine in 1 ml of ethyl acetate. The mixture was stirred for 1.5 hrat room temperature. The solution was diluted with ethyl acetate, washedwith water, saturated sodium chloride solution and dried over anhydroussodium sulfate. Filtration followed by evaporation of solvent providedan oil. The oil was purified by flash chromatography on silica gel(230-400 mesh; eluent: 30% ethyl acetate/hexane). Evaporation of thesolvent provided an oil, which as treated with ethereal hydrogenchloride to provide 34.8 mg (23.9%) of product, as the hydrochloride, mp160°-184°.

Analysis: Calculated for C₂₈ H₄₅ NO₈ HCl: 60.88%C, 8.10%H, 2.45%N,Found: 60.29%C, 7.93%H, 2.24%N.

EXAMPLE 107β-Acetoxy-8,13-epoxy-1α-(isopropylaminoacetoxy)-6β,9.alpha.-dihydroxylabd-14-en-11-onehydrochloride

To a stirred solution of 0.0301 g of7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in a stirredsolution of 3 ml of dry dichloromethane containing 0.106 ml ofdimethylaniline at 0°, under nitrogen, was added dropwise a solution of0.075 ml of bromoacetyl bromide in 3 ml of dry dichloromethane. Themixture was stirred 1 hr at 0°, poured into ice water, washed with icecold sat sodium bicarbonate solution, water and dried over anhydroussodium sulfate. Filtration followed by evaporation of solvent providedan oil. The oil was dissolved in 3 ml of dry dichloromethane and addeddropwise to a stirred solution of 0.300 g of isopropylamine in 3 ml ofethyl acetate. The mixture was stirred 2.5 hr at room temperature,poured into ice water, extracted with ethyl acetate, washed withsaturated sodium chloride solution and dried over anhydrous sodiumsulfate. Filtration followed by evaporation of solvent provided an oilwhich was flash chromatographed on 20 g of silica gel (230-400 mesh)(eluent: 70% ethyl acetate/hexane 0.1% ammonium hydroxide).Concentration of the appropriate fractions provided an oil. Treatment ofthe oil with ethereal hydrogen provided under 0.245 g (61.3%) ofproduct, as the hydrochloride, mp 154°-174°.

Analysis: Calculated for C₂₇ H₄₃ NO₇ HCl: 59.38%C, 8.12%H, 2.57%N,Found: 58.82%C, 8.05%H, 2.74%N.

EXAMPLE 117β-Acetoxy-8,13-epoxy-1α-(t-butylamino)acetoxy-6β,9α-dihydroxylabd-14-en-11-onehydrochloride

To a stirred solution of 106 mg of7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one and 0.036 mlof dimethylaniline in 1 ml of dry dichloromethane in an ice bath wasadded dropwise a solution of 0.025 ml of bromoacetyl bromide in 1 ml ofdry dichloromethane. The mixture was stirred 1 hr at ice bathtemperature. The reaction mixture was allowed to warm to roomtemperature, diluted with ethyl acetate, poured onto ice/water,extracted with ethyl acetate, washed with cold sat sodium bicarbonatesolution, water and dried over anhydrous sodium sulfate. Filtrationfollowed by evaporation of the solvent provided an oil. The oil wasdissolved in 1 ml of dichloromethane and added dropwise to a solution of0.105 g of t-butylamine in 1 ml of ethyl acetate. The mixture wasstirred at room temperature for 16 hrs, diluted with ethyl acetate,washed with water, sat sodium chloride solutions and dried overanhydrous sodium sulfate. Filtration followed by evaporation of thesolvent provided an oil. The oil was purified by flash chromatography(230-400 mesh silica gel; eluent: 30% ethyl actate/hexane).Concentration of the appropriate fractions provided an oil, which wastreated with ethereal hydrogen chloride, to provide 69.9 mg (48.3%) ofproduct, as the hydrochloride, mp 165°-179°.

Analysis: Calculated for C₂₉ H₄₅ NO₈ HCl: 60.04%C, 8.28%H, 2.50%N,Found: 59.73%C, 8.22%H, 2.26%N.

EXAMPLE 127β-Acetoxy-8,13-epoxy-1α-[2-(ethylamino)propionyloxy]-6β,9.alpha.-dihydroxylabd-14-en-11-onehydrochloride

To a stirred solution of 1.0 g of7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in 10 ml ofdichloromethane was added 0.35 ml of N,N-dimethylaniline. To the mixturewas added slowly, by syringe, a solution of 0.30 ml (0.618 g) ofbromopropionyl bromide in 10 ml of dichloromethane. The mixture wasstirred 1 hr at room temperature, cooled in an ice-bath, poured intoice/water/sodium bicarbonate and the mixture was extracted with ethylacetate. The extracts were washed with water, dried over anhydroussodium sulfate, filtered and concentrated to an oil. The oil wasdissolved in 10 ml of dichloromethane and added by syringe to a stirredsolution of excess monoethylamine in 10 ml of ethyl acetate in anice-bath. The solution was allowed to warm to room temperature andstirred for 3 hrs. The solution was poured into ice/water/ethyl acetateand extracted twice with ethyl acetate. The extracts were washed twicewith water, with saturated sodium chloride solution, dried overanhydrous sodium sulfate and filtered. Filtration followed byevaporation of the solvent provided an oil. The oil was dissolved in aminimum volume of 2% methanol/dichloromethane and flash chromatographedon 150 g of silica gel (230-400 mesh). The column was eluted as follows:1×400 ml 2% methanol/dichloromethane, 1×200 ml 2%methanol/dichloromethane, 3×100 ml 4% methanol/dichloromethane, 10×50 ml4% methanol dichloromethane. A diasteriomer was contained in the firsttwo 4% methanol/dichloromethane fractions. A mixture of diasteriomerswas contained in the third 4% methanol/dichlormethane fraction. A seconddiasteriomer was contained in fractions 4 through 6. The diasteriomerswere isolated. The diasteriomers were then combined, concentrated to anoil, dissolved in anhydrous ether and precipitated with etherealhydrogen chloride to provide 0.354 g (26.6%) of product, mp 160°-174°.

Analysis: Calculated for C₂₇ H₄₃ NO₈.HCl: 59.38%C, 8.12%H, 2.57%N,Found: 59.00%C, 7.94%H, 2.39%N.

EXAMPLE 137β-Acetoxy-8,13-epoxy-1α-[2-(morpholin-4-yl)propionyloxy]-6.beta.,9α-dihydroxylabd-14-en-11-onehydrochloride

To a stirred solution of 0.3 g of7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in 3 ml ofdichloromethane under nitrogen was added 0.106 ml of dimethylaniline.The solution was cooled to 0° and a solution of 0.090 ml of2-bromopropionyl bromide in 3 ml of dichloromethane was added dropwise.The solution was stirred 1 hr at 0°, poured into ice/sodiumbicarbonate/ethyl acetate and the mixture was extracted twice with ethylacetate. The extracts were washed with water, dried over anhydroussodium sulfate and filtered. Filtration followed by evaporation ofsolvent provided an oil. The oil was dissolved in 3 ml ofdichloromethane and added to a stirred solution of 0.3 g of morpholinein 3 ml of ethyl acetate. The solution was stirred at room temperaturefor 3 hr., poured into water/ice/ethyl acetate and the mixture wasextracted twice with ethyl acetate. The extracts were washed twice withwater and once with sodium chloride solution. The solution was driedover anhydrous sodium sulfate, filtered and concentrated to an oil. Theoil was dissolved in a minimum volume of 40% ethyl acetate/hexane andflash chromatographed on 150 g of silica gel (eluent: 10×50 ml of 40%ethyl acetate/hexane). Individual fractions were concentrated and thetwo diasteriomers were isolated. The fractions containing eitherdiasteriomer were then combined and the solvent was evaporated. Theresultant oil was dissolved in ether and precipitated with etherealhydrogen chloride to provide, after drying, 0.121 g (28%) of product, mp160°-170°.

Analysis: Calculated for C₂₉ H₄₅ NO₉.HCl: 59.22%C, 7.88%H, 2.38%N,Found: 59.53%C, 7.93%H, 2.17%N.

EXAMPLE 147β-Acetoxy-8,13-epoxy-1α-(4-methylpiperazin-1-yl)acetoxy-6β,9α-dihydroxylabd-14-en-11-onehydrochloride

To a stirred solution of 300 ml of7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in 3 ml ofdichloromethane containing 0.106 ml of dimethylaniline at 0° was addeddropwise a solution of 0.075 ml (0.175 g) of bromoacetyl bromide in 3 mlof dichloromethane. The mixture was stirred 1 hr at 0°, poured intoice/saturated sodium bicarbonate solution/ethyl acetate, and the mixturewas extracted with ethyl acetate. The extracts were washed with water,dried over anhydrous sodium sulfate and filtered. Filtration followed byevaporation of the solvent provided an oil. The oil was dissolved indichloromethane and added to a solution of 0.3 g of N-methylpiperazinein 3 ml of ethyl acetate. The mixture was stirred 2 hrs. at roomtemperature, poured onto ice/water/ethyl acetate and the layers wereseparated. The extracts were washed with water, saturated sodiumchloride solution and dried over anhydrous sodium sulfate. Filtrationfollowed by evaporation of solvent provided an oil. The oil wasdissolved in a minimum volume of 7% methanol/dichloromethane/0.1%ammonium hydroxide and flash chromatographed on silica gel (230-400mesh), eluent: 7% methanol/dichloromethane/0.1% ammonium hydroxide,followed by 10% methanol/dichloromethane/0.1% ammonium hydroxide.Evaporation of solvent from the appropriate fractions provided an oil,which was dissolved in 5% ethyl acetate/ether and precipitated withethereal hydrogen chloride to provide 0.242 g (56.3%) of product, mp189°-196° dec.

Analysis: Calculated for C₂₉ H₄₆ N₂ O₈.HCl: 59.32%C, 8.07%H, 4.77%N,Found: 59.12%C, 8.02%H, 4.77%N. ##STR6##

We claim:
 1. A compound of the formulawherein R₁ is R₂ R₃ NCHR₄ COwherein R₂ is hydrogen, loweralkyl or benzyl, R₃ is hydrogen orloweralkyl and R₄ is hydrogen, loweralkyl or benzyl; R₂ and R₃ takentogether with the nitrogen atom to which they are attached form a groupof the formula ##STR7## wherein X is CO, O, S, SO, SO₂ ; a group of theformula CHR₉ wherein R₉ is hydrogen, loweralkyl or a group of theformula OR₁₀ wherein R₁₀ is hydrogen or COR₁₁ wherein R₁₁ is loweralkyl;or a group of the formula NR₁₂ wherein R₁₂ is loweralkyl; n is 1 or 0;and R₆ and R₇ taken together form a group of the formula CO or SO; theoptical and geometric isomers thereof, or a pharmaceutically acceptableacid addition salt thereof.
 2. A compound according to claim 1 whereinR₂ and R₃ are hydrogen or loweralkyl.
 3. A compound according to claim 1wherein R₂ is hydrogen and R₃ is loweralkyl.
 4. A compound according toclaim 1 wherein R₂ and R₃ taken together with the nitrogen atom to whichthey are attached form a group of the formula ##STR8## wherein X is CO,O, S, SO, SO₂, a group of the formula CHR₉ wherein R₉ is hydrogen,loweralkyl or a group of the formula OR₁₀ wherein R₁₀ is hydrogen or agroup of the formula COR₁₁ wherein R₁₁ is loweralkyl, or a group of theformula NR₁₂ wherein R₁₂ is loweralkyl, and n is 0 or
 1. 5. A compoundaccording to claim 1 wherein R₄ is hydrogen or loweralkyl.
 6. A compoundaccording to claim 1 wherein R₄ is benzyl.
 7. An intraocular pressurereducing composition comprising an inert adjuvant and as the activeingredient, an amount effective in reducing intraocular pressure of acompound of the formula ##STR9## wherein R₁ is R₂ R₃ NCHR₄ CO wherein R₂is hydrogen, loweralkyl or benzyl, R₃ is hydrogen or loweralkyl and R₄is hydrogen, loweralkyl or benzyl; R₂ and R₃ taken together with thenitrogen atom to which they are attached form a group of the formula##STR10## wherein X is CO, O, S, SO, SO₂, a group of the formula CHR₉wherein R₉ is hydrogen, loweralkyl or a group of the formula OR₁₀wherein R₁₀ is hydrogen or COR₁₁ wherein R₁₁ is loweralkyl, or a groupof the formula NR₁₂ wherein R₁₂ is loweralkyl; n is 0 or 1; and R₆ andR₇ taken together form a group of the formula CO or SO; the optical andgeometric isomers thereof or a pharmaceutically acceptable acid additionsalt thereof.
 8. A method of reducing intraocular pressure in mammalscomprising administering to a mammal requiring intraocular pressurereduction an intraocular pressure reducing effective amount of acompound of the formula ##STR11## wherein R₁ is R₂ R₃ NCHR₄ CO whereinR₂ is hydrogen, loweralkyl or benzyl, R₃ is hydrogen or loweralkyl andR₄ is hydrogen, loweralkyl or benzyl; R₂ and R₃ taken together with thenitrogen atom to which they are attached form a group of the formula##STR12## wherein X is CO, O, S, SO, SO₂, a group of the formula CHR₉wherein R₉ is hydrogen, loweralkyl or a group of the formula OR₁₀wherein R₁₀ is hydrogen or COR₁₁ wherein R₁₁ is loweralkyl, or a groupof the formula NR₁₂ wherein R₁₂ is loweralkyl; n is 0 or 1; and R₆ andR₇ taken together form a group of the formula CO or SO; the optical andgeometric isomers thereof or a pharmaceutically acceptable acid additionsalt thereof.